Mr. Horsman et al., NICOTINAMIDE AS A RADIOSENSITIZER IN TUMORS AND NORMAL-TISSUES - THE IMPORTANCE OF DRUG DOSE AND TIMING, Radiotherapy and oncology, 45(2), 1997, pp. 167-174
Background and purpose: Nicotinamide is a radiation sensitizer current
ly undergoing clinical testing. This was an experimental study to dete
rmine the importance of drug dose and time interval between drug admin
istration and irradiation for radiosensitization. Materials and method
s: Nicotinamide (50-500 mg/kg) was injected intraperitoneally into CDF
1 or C3H mice and drug plasma pharmacokinetics were determined by HPLC
. Radiosensitization was measured in rumours and normal tissues after
local irradiation. The tumours were a C3H mammary carcinoma, the KHT s
arcoma and the SCCVII carcinoma. Tumour response was assessed using ei
ther growth delay (C3H) or clonogenic survival (KHT/SCCVII). Normal ti
ssue toxicities evaluated included early responding skin (development
of moist desquamation of the foot) and late responding bladder (reserv
oir function estimated by cystometry) and lung (ventilation rate measu
red by plethysmography). Results: All nicotinamide peak plasma concent
rations were seen within 30 min after injection. Irradiating tumours a
t peak times resulted in enhancement ratios (ERs) of 1.27 (C3H), 1.75
(KHT) and 1.45 (SCCVII) with high nicotinamide doses and 1.27 (C3H), 1
.28 (KHT) and 1.36 (SCCVII) after giving clinically relevant doses (10
0-200 mg/kg). Lower ERs were observed when the time interval between d
rug injection and irradiation was increased beyond the peak time. Irra
diating normal tissues at peak times after injecting 100-200 mg/kg nic
otinamide gave ERs of 1.20 (skin), 0.90 (bladder) and 1.02 (lung). Con
clusions: Clinically achievable doses of nicotinamide will enhance tum
our radiation damage while having minimal effects in normal tissues, b
ut for the best tumour effect radiation should be given at the time of
peak plasma drug concentrations. (C) 1997 Elsevier Science Ireland Lt
d.